Neurocognitive deficits, particularly in the domain of working memory/executive processes, are thought to play major roles in the development of schizophrenia and associated deficits in role functioning. We propose a novel translational behavioral science strategy probing the functional architecture of working memory and its disturbance in the developmental course of schizophrenia. We aim to identify major functional subdivisions within working memory using behavioral paradigms drawn from cognitive psychology during trial-based functional magnetic resonance imaging (fMRI) studies with healthy subjects and to translate these paradigms into short-term longitudinal fMRI studies of prodromal and first-episode schizophrenic patients to determine the possible differential relevance of disturbances in specific aspects of these systems to the prediction of schizophrenia onset and social-occupational outcome after the first year of psychosis. Our basic science goals are to improve our understanding of the cognitive neuroscience of working memory, focusing in particular on the proposed distinction between maintenance- versus manipulation-related processes and on processes associated with relational binding of elements held in working memory. We expect to detect participation of a number of interacting brain systems in these functions, including areas in dorsolateral prefrontal, inferior prefrontal, posterior parietal, and cingulate cortex, but we also expect to observe differential involvement of dorsolateral prefrontal cortex in executive-related working memory processing and in relational binding operations. Our clinical aims are to improve our understanding of the nature, timing of onset, course, and neurophysiologic correlates of working memory disturbances in the pre-onset and early post-onset phases of schizophrenia and to elucidate the roles of these disturbances in the development of impaired social and work functioning in these patients. We expect to detect differential deficits in behavioral and physiologic indicators of executive-related working memory processing and relational binding in the patient groups. Deterioration in these functions over time should predict a higher risk for conversion to schizophrenia among prodromal patients and poorer social and work outcome after the first year of psychosis in first-episode patients. This information will improve theoretical specification of the nature of working memory disturbances in the pathophysiology of schizophrenia and can be applied in future prodromal research to facilitate prediction of schizophrenia and in designing strategies for primary or secondary prevention. This information will also be pertinent to the development of strategies either to prevent or attenuate social and occupational impairments in schizophrenia or compensate for them by optimizing on intact skill acquisition systems.